Comparison of efficacy and side effects of epidural tramadol and morphine in patients undergoing laminectomy: a repeated dose study. (17/258)

Tramadol acts through multiple mechanisms and has a low risk of post operative respiratory depression. We compared the efficacy of epidural tramadol with that of morphine for postoperative analgesia in these patients. The demographic data and the summed pain intensity difference scores (SPID) were similar in both the groups. The time to first supplementary dose was significantly shorter in the tramadol group compared to the morphine group (p<0.05). No patient in either group suffered respiratory depression.  (+info)

Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. (18/258)

The metabolism of cis-tramadol has been studied in human liver microsomes and in cDNA-expressed human cytochrome P-450 (CYP) isoforms. Human liver microsomes catalyzed the NADPH-dependent metabolism of tramadol to the two primary tramadol metabolites, namely, O-desmethyl-tramadol (metabolite M1) and N-desmethyl-tramadol (metabolite M2). In addition, tramadol was also metabolized to two minor secondary metabolites (each comprising < or =3.0% of total tramadol metabolism), namely, N,N-didesmethyl-tramadol (metabolite M3) and N,O-didesmethyl-tramadol (metabolite M5). Kinetic analysis revealed that multiple CYP enzymes were involved in the metabolism of tramadol to both M1 and M2. For the high-affinity enzymes involved in M1 and M2 formation, K(m) values were 116 and 1021 microM, respectively. Subsequent reaction phenotyping studies were performed with a tramadol substrate concentration of 250 microM. In studies with characterized human liver microsomal preparations, good correlations were observed between tramadol metabolism to M1 and M2 and enzymatic markers of CYP2D6 and CYP2B6, respectively. Tramadol was metabolized to M1 by cDNA-expressed CYP2D6 and to M2 by CYP2B6 and CYP3A4. Tramadol metabolism in human liver microsomes to M1 and M2 was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. In summary, this study demonstrates that cis-tramadol can be metabolized to tramadol metabolites M1, M2, M3, and M5 in human liver microsomal preparations. By kinetic analysis and the results of the reaction phenotyping studies, tramadol metabolism in human liver is catalyzed by multiple CYP isoforms. Hepatic CYP2D6 appears to be primarily responsible for M1 formation, whereas M2 formation is catalyzed by CYP2B6 and CYP3A4.  (+info)

Influence of tramadol on morphine discriminative behavior in rats. (19/258)

AIM: To study the potential of the psychological dependence of tramadol. METHODS: Rats were trained to discriminate 4.0 mg/kg morphine, and to discriminate 0.5 mg/kg methamphetamine (MA) from saline under a fixed-ratio (FR10) schedule of reinforcement. After they acquired the discrimination, different doses of tramadol were used to substitute for training dose of morphine and MA. Naltrexone was injected concomitantly with tramadol. RESULTS: Tramadol fully substituted morphine at a dose of 32 mg/kg or higher. The ED50 value of the discriminative effects of tramadol was 20.94 mg/kg, higher than that of morphine (2.04 mg/kg, P < 0.01). MA failed to generalize to tramadol at the doses tested. Naltrexone antagonized the discriminative response of tramadol. CONCLUSION: Tramadol can substitute for morphine in morphine discriminative rats. The discriminative stimulus effects of tramadol are mediated by a mu opioid mechanism.  (+info)

Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. (20/258)

Tramadol is a widely used, centrally acting analgesic, but its mechanisms of action are not completely understood. Muscarinic receptors are known to be involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. This study investigated the effects of tramadol on muscarinic receptors by using two different systems, i.e., a Xenopus laevis oocyte expression system and cultured bovine adrenal medullary cells. Tramadol (10 nM-100 microM) inhibited acetylcholine-induced currents in oocytes expressing the M1 receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. On the other hand, tramadol did not inhibit the current induced by AlF4-, a direct activator of GTP-binding protein. In cultured bovine adrenal medullary cells, tramadol (100 nM-100 microM) suppressed muscarine-induced cyclic GMP accumulation. Moreover, tramadol inhibited the specific binding of [3H]quinuclidinyl benzilate (QNB). Scatchard analysis showed that tramadol increases the apparent dissociation constant (Kd) value without changing the maximal binding (Bmax), indicating competitive inhibition. These findings suggest that tramadol at clinically relevant concentrations inhibits muscarinic receptor function via QNB-binding sites. This may explain the neuronal function and anticholinergic effect of tramadol.  (+info)

Analgesic efficacy of tramadol 2 mg kg(-1) for paediatric day-case adenoidectomy. (21/258)

We studied the analgesic efficacy of tramadol 2 mg kg(-1) for post-operative analgesia after day-case adenoidectomy in children aged 1-3 yr. Eighty children were allocated randomly to receive tramadol 2 mg kg(-1) i.v. or placebo immediately after induction of anaesthesia. Anaesthesia was induced with alfentanil 10 microg kg(-1) and propofol 4 mg kg(-1) followed by mivacurium 0.2 mg kg(-1) for tracheal intubation. Anaesthesia was continued with sevoflurane in nitrous oxide and oxygen. All children were given ibuprofen rectally at approximately 10 mg kg(-1) before the start of surgery. Post-operative pain and recovery assessments were performed by a nurse blinded to the analgesic treatment using the Aldrete recovery score, the pain/discomfort scale and measurement of recovery times. Rescue medication (pethidine in increments of 5 mg i.v.) was administered according to the pain scores. A post-operative questionnaire was used to evaluate the need for analgesia at home up to 24 h after operation. Rescue analgesic at home was rectal or oral ibuprofen 125 mg. Children in the tramadol group required fewer pethidine doses than those in the placebo group (P = 0.014). Forty-five per cent of children receiving tramadol did not require post-operative analgesia at all compared with 15% of children receiving placebo (P = 0.003). Recovery times and the incidence of adverse effects were similar in the two groups in the recovery room and at home. The requirement for rectal ibuprofen at home did not differ between groups.  (+info)

Tramadol drops in children: analgesic efficacy, lack of respiratory effects, and normal recovery times. (22/258)

Tramadol hydrochloride is a racemic mixture of two enantiomers. It has analgesic activity suitable for mild to moderate pain, part of its analgesic activity being modulated via mu receptors. Adult studies have raised the question of increased electroencephalographic activity. The study examined the analgesic efficacy, respiratory effects, and behavior plus recovery-influencing properties of tramadol in the pediatric patient. Day-case dental extraction children, aged 4-7 years having 6 or more extractions, were studied. Tramadol drops, 3 mg/kg, plus oral midazolam, 0.5 mg/kg, were administered 30 minutes prior to a sevoflurane in N2O and O2 anesthetic. Forty children received this premedication treatment (T) and 10 entered a placebo control group (P), where no tramadol was administered. Entry was random, double blind, and parallel. Analgesic efficacy was measured using the Oucher face pain scale (OFPS), with responders scoring three or less. Respiration was measured by rate and oxygen saturation. Behavior and ease of mask induction were assessed on a 4-point scale. Recovery was measured with the Aldrete scale. Parameters were measured from 30 minute preanesthetic to 120 minute postanesthetic. Analgesic efficacy was shown, with an OFPS score of 11.42 (SD 18.66) (T) and 29.80 (SD 25.14) (P) (P < .05). Responders on tramadol were 77.5% versus 0% on placebo (P < .05). No respiratory depression was seen; rates and oxygen saturations were the same preanesthetic and postanesthetic. Similarly, the two groups had no cardiovascular differences. Preanesthetic behavior patterns were the same (P > .05), with 85% of the tramadol group being drowsy but awake versus 90% in the placebo group. Similarly satisfactory induction behavior was seen in 95% of the tramadol group and 90% of the placebo group. Recovery times were 48.6 minutes (SD 32.3) (T) and 43.1 minutes (SD 32.5) (P) (P > .05). It is concluded that tramadol at 3 mg/kg has no clinical respiratory depressant effect and that behavior and recovery times are unaffected. Analgesic efficacy is demonstrated.  (+info)

Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. (23/258)

The effect of tramadol on the plasma glucose level of streptozotocin (STZ)-induced diabetic rats was investigated. A dose-dependent lowering of plasma glucose was seen in the fasting STZ-induced diabetic rats 30 min after intravenous injection of tramadol. This effect of tramadol was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptors. However, response to tramadol was not changed in STZ-induced diabetic rats receiving p-chlorophenylalanine at a dose sufficient to deplete endogenous 5-hydroxytrptamine (5-HT). Therefore, mediation of 5-HT in this action of tramadol is ruled out. In isolated soleus muscle, tramadol enhanced the uptake of radioactive glucose in a concentration-dependent manner. The stimulatory effects of tramadol on glycogen synthesis were also seen in hepatocytes isolated from STZ-induced diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid mu-receptors. The mRNA and protein levels of the subtype 4 form of glucose transporter in soleus muscle were increased after repeated treatments for 4 days with tramadol in STZ-induced diabetic rats. Moreover, similar repeated treatments with tramadol reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase in the liver of STZ-induced diabetic rats. These results suggest that activation of opioid mu-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.  (+info)

Tramadol and acetaminophen tablets for dental pain. (24/258)

The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2.7) monotherapy groups. A new combination analgesic, tramadol/APAP, is superior to tramadol or APAP alone with respect to pain relief and duration of action. It is also superior to tramadol alone with respect to time to onset.  (+info)